tbuckley/cabot-search huggingface dataset:
The ribosomal protein S6 kinase alpha-1 (RPS6KA1) induces resistance to venetoclax/azacitidine in acute myeloid leukemia
Authors: Katharina Weidenauer, Christina Schmidt, Christian Rohde, Cornelius Pauli, Maximilian F. Blank, Daniel Heid, Alexander Waclawiczek, Anika Corbacioglu, Stefanie Göllner, Michelle Lotze, Lisa Vierbaum, Simon Renders, Jeroen Krijgsveld, Simon Raffel, Tim Sauer, Andreas Trumpp, Caroline Pabst, Carsten Müller-Tidow, Maike Janssen
Journal: Leukemia (2023)

Abstract Venetoclax/azacitidine combination therapy is effective in acute myeloid leukemia (AML) and tolerable for older, multimorbid patients. Despite promising response rates, many patients do not achieve sustained remission or are upfront refractory. Identification of resistance mechanisms and additional therapeutic targets represent unmet clinical needs. By using a genome-wide CRISPR/Cas9 library screen targeting 18,053 protein- coding genes in a human AML cell line, various genes conferring resistance to combined venetoclax/azacitidine treatment were identified. The ribosomal protein S6 kinase A1 (RPS6KA1) was among the most significantly depleted sgRNA-genes in venetoclax/azacitidine- treated AML cells. Addition of the RPS6KA1 inhibitor BI-D1870 to venetoclax/azacitidine decreased proliferation and colony forming potential compared to venetoclax/azacitidine alone. Furthermore, BI-D1870 was able to completely restore the sensitivity of OCI-AML2 cells with acquired resistance to venetoclax/azacitidine. Analysis of cell surface markers revealed that RPS6KA1 inhibition efficiently targeted monocytic blast subclones as a potential source of relapse upon venetoclax/azacitidine treatment. Taken together, our results suggest RPS6KA1 as mediator of resistance towards venetoclax/azacitidine and additional RPS6KA1 inhibition as strategy to prevent or overcome resistance.
SGLT2 inhibitor empagliflozin downregulates miRNA-34a-5p and targets GREM2 to inactivate hepatic stellate cells and ameliorate non-alcoholic fatty liver disease-associated fibrosis
Authors: Yunfeng Shen, Lidan Cheng, Minxuan Xu, Wei Wang, Zhiping Wan, Haixia Xiong, Wanrong Guo, Mengyin Cai, Fen Xu
Journal: Metabolism (2023)
Polymeric in situ forming depots for long-acting drug delivery systems
Authors: Anjali K. Pandya, Lalitkumar K. Vora, Chukwuebuka Umeyor, Dhanashree Surve, Akanksha Patel, Swati Biswas, Ketankumar Patel, Vandana B. Patravale
Journal: Advanced Drug Delivery Reviews (2023)
Human resident liver myeloid cells protect against metabolic stress in obesity
Authors: Emelie Barreby, Benedikt Strunz, Sebastian Nock, Léa Naudet, Joanne X. Shen, Helene Johansson, Isabella Sönnerborg, Junjie Ma, Egon Urgard, Laura J. Pallett, Yizhou Hu, Achilleas Fardellas, Valerio Azzimato, Ana Vankova, Laura Levi, Cecilia Morgantini, Mala K. Maini, Per Stål, Stephan P. Rosshart, Jonathan M. Coquet, Greg Nowak, Erik Näslund, Volker M. Lauschke, Ewa Ellis, Niklas K. Björkström, Ping Chen, Myriam Aouadi
Journal: Nature Metabolism (2023)

Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease (NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD.
Spatiotemporal transcriptomic maps of whole mouse embryos at the onset of organogenesis
Authors: Abhishek Sampath Kumar, Luyi Tian, Adriano Bolondi, Amèlia Aragonés Hernández, Robert Stickels, Helene Kretzmer, Evan Murray, Lars Wittler, Maria Walther, Gabriel Barakat, Leah Haut, Yechiel Elkabetz, Evan Z. Macosko, Léo Guignard, Fei Chen, Alexander Meissner
Journal: Nature Genetics (2023)

Abstract Spatiotemporal orchestration of gene expression is required for proper embryonic development. The use of single-cell technologies has begun to provide improved resolution of early regulatory dynamics, including detailed molecular definitions of most cell states during mouse embryogenesis. Here we used Slide-seq to build spatial transcriptomic maps of complete embryonic day (E) 8.5 and E9.0, and partial E9.5 embryos. To support their utility, we developed sc3D, a tool for reconstructing and exploring three-dimensional ‘virtual embryos’, which enables the quantitative investigation of regionalized gene expression patterns. Our measurements along the main embryonic axes of the developing neural tube revealed several previously unannotated genes with distinct spatial patterns. We also characterized the conflicting transcriptional identity of ‘ectopic’ neural tubes that emerge in Tbx6 mutant embryos. Taken together, we present an experimental and computational framework for the spatiotemporal investigation of whole embryonic structures and mutant phenotypes.
A prognostic risk score for development and spread of chronic pain
Authors: Christophe Tanguay-Sabourin, Matt Fillingim, Gianluca V. Guglietti, Azin Zare, Marc Parisien, Jax Norman, Hilary Sweatman, Ronrick Da-ano, Eveliina Heikkala, John C. S. Breitner, Julien Menes, Judes Poirier, Jennifer Tremblay-Mercier, Jordi Perez, Jaro Karppinen, Sylvia Villeneuve, Scott J. Thompson, Marc O. Martel, Mathieu Roy, Luda Diatchenko, Etienne Vachon-Presseau
Journal: Nature Medicine (2023)

Chronic pain is a complex condition influenced by a combination of biological, psychological and social factors. Using data from the UK Biobank (n = 493,211), we showed that pain spreads from proximal to distal sites and developed a biopsychosocial model that predicted the number of coexisting pain sites. This data-driven model was used to identify a risk score that classified various chronic pain conditions (area under the curve (AUC) 0.70-0.88) and pain-related medical conditions (AUC 0.67-0.86). In longitudinal analyses, the risk score predicted the development of widespread chronic pain, the spreading of chronic pain across body sites and high-impact pain about 9 years later (AUC 0.68-0.78). Key risk factors included sleeplessness, feeling 'fed-up', tiredness, stressful life events and a body mass index >30. A simplified version of this score, named the risk of pain spreading, obtained similar predictive performance based on six simple questions with binarized answers. The risk of pain spreading was then validated in the Northern Finland Birth Cohort (n = 5,525) and the PREVENT-AD cohort (n = 178), obtaining comparable predictive performance. Our findings show that chronic pain conditions can be predicted from a common set of biopsychosocial factors, which can aid in tailoring research protocols, optimizing patient randomization in clinical trials and improving pain management.
Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial
Authors: Bertrand Routy, John G. Lenehan, Wilson H. Miller, Rahima Jamal, Meriem Messaoudene, Brendan A. Daisley, Cecilia Hes, Kait F. Al, Laura Martinez-Gili, Michal Punčochář, Scott Ernst, Diane Logan, Karl Belanger, Khashayar Esfahani, Corentin Richard, Marina Ninkov, Gianmarco Piccinno, Federica Armanini, Federica Pinto, Mithunah Krishnamoorthy, Rene Figueredo, Pamela Thebault, Panteleimon Takis, Jamie Magrill, LeeAnn Ramsay, Lisa Derosa, Julian R. Marchesi, Seema Nair Parvathy, Arielle Elkrief, Ian R. Watson, Rejean Lapointe, Nicola Segata, S.M. Mansour Haeryfar, Benjamin H. Mullish, Michael S. Silverman, Jeremy P. Burton, Saman Maleki Vareki
Journal: Nature Medicine (2023)
T follicular helper cells and T peripheral helper cells in rheumatic and musculoskeletal diseases
Authors: Mitsuhiro Akiyama, Waleed Alshehri, Keiko Yoshimoto, Yuko Kaneko
Journal: Annals of the Rheumatic Diseases (2023)

Recent technological progress has greatly advanced our understanding of human immunology. In particular, the discovery of human T follicular helper (Tfh) and T peripheral helper (Tph) cells has significantly advanced our understanding of human adaptive immune system. Tfh and Tph cells share similar molecular characteristics and both play critical roles in B cell differentiation and maturation. However, they differ in their functional properties, such as chemokine receptor expression and cytokine production. As a result, Tfh cells are mainly involved in B cell differentiation and maturation in germinal centres of secondary lymphoid tissues, while Tph cells are involved in B cell differentiation and tissue damage in peripheral inflammatory lesions. Importantly, the involvement of Tfh and Tph cells in the pathogenesis of rheumatic and musculoskeletal diseases has become clear. In rheumatoid arthritis and systemic lupus erythematosus, Tph cell infiltration is predominant in peripheral inflammatory lesions, whereas Tfh cell infiltration is predominant in the affected lesions of IgG4-related disease. Therefore, the contribution of Tfh and Tph cells to the development of rheumatic and musculoskeletal diseases varies depending on each disease. In this review, we provide an overview of human Tfh and Tph cells and summarise the latest findings on these novel T cell subsets in various rheumatic and musculoskeletal diseases.
Mechanisms of hypoxaemia in severe pulmonary hypertension associated with COPD
Authors: Lucilla Piccari, Isabel Blanco, Yolanda Torralba, Ebymar Arismendi, Concepción Gistau, Ana Ramírez, Elena Gimeno-Santos, Josep Roca, Felip Burgos, Roberto Rodríguez-Roisín, Joan Albert Barberà
Journal: European Respiratory Journal (2023)

Pulmonary hypertension (PH) is a frequent complication of chronic obstructive pulmonary disease (COPD) with poor prognosis, especially in its severe form [1]. Accordingly, current guidelines distinguish patients with severe PH from those with moderate PH [2]. Patients with COPD and severe PH often present with worse hypoxaemia than those with moderate PH, despite having milder airflow obstruction [3–5]. The mechanisms underlying severe hypoxaemia in these patients have not been elucidated. This study aimed to analyse the determinants of hypoxaemia in severe PH associated with COPD by assessing ventilation-perfusion (VA/Q) relationships with the multiple inert gas elimination technique (MIGET). Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Lucilla Piccari has received research funding from and served as a speaker for Janssen-Cilag and Ferrer International, participated in advisory boards for Janssen-Cilag, Ferrer International and United Therapeuthics as well as received support for attending congresses from Janssen-Cilag, Merck Sharp & Dome and Ferrer International, all of which not related to this manuscript. Conflict of interest: Isabel Blanco reports lecture honoraria from Janssen, MSD and Ferrer; outside the submitted work. Yolanda Torralba reports lecture honoraria from TEVA; outside the submitted work. Conflict of interest: Felip Burgos reports consulting fees from Scientific Advisory Board Medical Graphics Diagnostics, outside the submitted work. Conflict of interest: Roberto Rodríguez-Roisín reports grants from CHIESI Spain, outside the submitted work. Conflict of interest: Joan Albert Barberà reports consulting fees from Merck Sharp & Dome, Janssen-Cilag, Acceleron Pharma; lecture honoraria from Ferrer International, Janssen-Cilag, Merck Sharp & Dome; travel support from Merck Sharp & Dome, Janssen-Cilag; outside the submitted work. All other authors have nothing to disclose.
European Respiratory Society statement on frailty in adults with chronic lung disease
Authors: Christian R. Osadnik, Lisa J. Brighton, Chris Burtin, Matteo Cesari, Lies Lahousse, Will D.C. Man, Alessandra Marengoni, Andreja Sajnic, Jonathan P. Singer, Lies ter Beek, Ioanna Tsiligianni, Janos T. Varga, Stefano Pavanello, Matthew Maddocks
Journal: European Respiratory Journal (2023)

Frailty is a complex, multidimensional syndrome characterised by a loss of physiological reserves that increases a person's susceptibility to adverse health outcomes. Most knowledge regarding frailty originates from geriatric medicine; however, awareness of its importance as a treatable trait for people with chronic respiratory disease (including asthma, COPD and interstitial lung disease) is emerging. A clearer understanding of frailty and its impact in chronic respiratory disease is a prerequisite to optimise clinical management in the future. This unmet need underpins the rationale for undertaking the present work. This European Respiratory Society statement synthesises current evidence and clinical insights from international experts and people affected by chronic respiratory conditions regarding frailty in adults with chronic respiratory disease. The scope includes coverage of frailty within international respiratory guidelines, prevalence and risk factors, review of clinical management options (including comprehensive geriatric care, rehabilitation, nutrition, pharmacological and psychological therapies) and identification of evidence gaps to inform future priority areas of research. Frailty is underrepresented in international respiratory guidelines, despite being common and related to increased hospitalisation and mortality. Validated screening instruments can detect frailty to prompt comprehensive assessment and personalised clinical management. Clinical trials targeting people with chronic respiratory disease and frailty are needed.
Single-inhaler triple<i>versus</i>dual bronchodilator therapy for GOLD group E and other exacerbating patients with COPD: real-world comparative effectiveness and safety
Authors: Samy Suissa
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>A real-world study supports the new 2023 GOLD recommendation that single-inhaler triple therapy be reserved for group E and other exacerbating COPD patients with blood eosinophils count &gt;300, otherwise it is not more effective and is riskier than LAMA-LABA</b> https://bit.ly/3NpWtZC
Status of New Vaccine Introduction — Worldwide, 2016–2021
Authors: Gurpreet Kaur, Rebecca M. Casey, Jaymin C. Patel, Paul Bloem, Jenny A. Walldorf, Terri B. Hyde
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

This report describes the status of introductions globally for eight World Health Organization (WHO)-recommended new and underutilized vaccines, comprising 10 individual vaccine antigens. By 2021, among 194 countries worldwide, 33 (17%) provided all of these 10 WHO-recommended antigens as part of their routine immunization schedules; only one low-income country had introduced all of these recommended vaccines. Universal hepatitis B birth dose; human papillomavirus vaccine; rotavirus vaccine; and diphtheria, tetanus, and pertussis-containing vaccine first booster dose have been introduced by 57%, 59%, 60%, and 72% of all countries worldwide, respectively. Pneumococcal conjugate vaccine, rubella-containing vaccine, measles-containing vaccine second dose, and Haemophilus influenzae type b vaccine have been introduced by 78%, 89%, 94%, and 99% of all countries, respectively. The annual rate of new vaccine introductions declined precipitously when the COVID-19 pandemic started, from 48 in 2019 to 15 in 2020 before rising to 26 in 2021. Increased efforts to accelerate new and underutilized vaccine introductions are urgently needed to improve universal equitable access to all recommended vaccines to achieve the global Immunization Agenda 2021-2030 (IA2030) targets.
<i>QuickStats:</i> Number of Deaths from Hornet, Wasp, and Bee Stings* Among Males and Females — National Vital Statistics System, United States, 2011–2021
Authors: Jiaquan Xu
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

During 2011-2021, a total of 788 deaths from hornet, wasp, and bee stings occurred (an average of 72 deaths per year).The annual number of deaths ranged from 59 (2012) to 89 (2017).Overall, 84% of deaths occurred among males.
Intronic small nucleolar RNAs regulate host gene splicing through base pairing with their adjacent intronic sequences
Authors: Danny Bergeron, Laurence Faucher-Giguère, Ann-Kathrin Emmerichs, Karine Choquet, Kristina Sungeun Song, Gabrielle Deschamps-Francoeur, Étienne Fafard-Couture, Andrea Rivera, Sonia Couture, L. Stirling Churchman, Florian Heyd, Sherif Abou Elela, Michelle S. Scott
Journal: Genome biology (2023)

Abstract Background Small nucleolar RNAs (snoRNAs) are abundant noncoding RNAs best known for their involvement in ribosomal RNA maturation. In mammals, most expressed snoRNAs are embedded in introns of longer genes and produced through transcription and splicing of their host. Intronic snoRNAs were long viewed as inert passengers with little effect on host expression. However, a recent study reported a snoRNA influencing the splicing and ultimate output of its host gene. Overall, the general contribution of intronic snoRNAs to host expression remains unclear. Results Computational analysis of large-scale human RNA-RNA interaction datasets indicates that 30% of detected snoRNAs interact with their host transcripts. Many snoRNA-host duplexes are located near alternatively spliced exons and display high sequence conservation suggesting a possible role in splicing regulation. The study of the model SNORD2-EIF4A2 duplex indicates that the snoRNA interaction with the host intronic sequence conceals the branch point leading to decreased inclusion of the adjacent alternative exon. Extended SNORD2 sequence containing the interacting intronic region accumulates in sequencing datasets in a cell-type-specific manner. Antisense oligonucleotides and mutations that disrupt the formation of the snoRNA-intron structure promote the splicing of the alternative exon, shifting the EIF4A2 transcript ratio away from nonsense-mediated decay. Conclusions Many snoRNAs form RNA duplexes near alternative exons of their host transcripts, placing them in optimal positions to control host output as shown for the SNORD2-EIF4A2 model system. Overall, our study supports a more widespread role for intronic snoRNAs in the regulation of their host transcript maturation.
Tumor-associated myeloid cells in cancer immunotherapy
Authors: Xinyu Cheng, Huilan Wang, Zhongyu Wang, Bo Zhu, Haixia Long
Journal: Journal of Hematology & Oncology (2023)

Tumor-associated myeloid cells (TAMCs) are among the most important immune cell populations in the tumor microenvironment, and play a significant role on the efficacy of immune checkpoint blockade. Understanding the origin of TAMCs was found to be the essential to determining their functional heterogeneity and, developing cancer immunotherapy strategies. While myeloid-biased differentiation in the bone marrow has been traditionally considered as the primary source of TAMCs, the abnormal differentiation of splenic hematopoietic stem and progenitor cells, erythroid progenitor cells, and B precursor cells in the spleen, as well as embryo-derived TAMCs, have been depicted as important origins of TAMCs. This review article provides an overview of the literature with a focus on the recent research progress evaluating the heterogeneity of TAMCs origins. Moreover, this review summarizes the major therapeutic strategies targeting TAMCs with heterogeneous sources, shedding light on their implications for cancer antitumor immunotherapies.
Mimicking the Graded Wavy Structure of the Anterior Cruciate Ligament (Adv. Healthcare Mater. 17/2023)
Authors: Sandra Camarero‐Espinosa, Huipin Yuan, Pieter J. Emans, Lorenzo Moroni
Journal: Advanced Healthcare Materials (2023)

Tissue Regeneration The anterior cruciate ligament is characterized by its zonal structure. Electrospinning enables the fabrication of triphasic scaffolds that mimic the structure of the native ligament; with aligned and flattened extremes and an aligned and wavy core. In article 2203023 by Lorenzo Moroni and co-workers, the different phases of the scaffold lead to distinct cellular arrangements and the formation of a coherent tissue in vitro and in vivo.
Keeping It Organized: Multicompartment Constructs to Mimic Tissue Heterogeneity (Adv. Healthcare Mater. 17/2023)
Authors: Alvaro Sanchez‐Rubio, Vineetha Jayawarna, Emily Maxwell, Matthew J. Dalby, Manuel Salmeron‐Sanchez
Journal: Advanced Healthcare Materials (2023)

Tissue Engineering When engineering tissues in vitro it is essential to mimic the heterogeneity present in native tissues, both in composition and biological components. While different approaches and manufacturing technologies are used in literature, bioprinting holds great promise, being able to recapitulate complex architectural 3D features and use bioinks to support biological requirements. These considerations are reviewed in article 2202110 by Manuel Salmeron-Sanchez.
AIPH‐Encapsulated Thermo‐Sensitive Liposomes for Synergistic Microwave Ablation and Oxygen‐Independent Dynamic Therapy (Adv. Healthcare Mater. 17/2023)
Authors: Wenjie Zhang, Hu Zhou, Deyan Gong, Haitao Wu, Xiang Huang, Zhaohua Miao, Hu Peng, Zhengbao Zha
Journal: Advanced Healthcare Materials (2023)
Enhancing Pt(IV) Complexes' Anticancer Activity upon Encapsulation in Stimuli‐Responsive Nanocages (Adv. Healthcare Mater. 17/2023)
Authors: María Sancho‐Albero, Giorgio Facchetti, Nicolò Panini, Marina Meroni, Ezia Bello, Isabella Rimoldi, Massimo Zucchetti, Roberta Frapolli, Luisa De Cola
Journal: Advanced Healthcare Materials (2023)

Tumor Reduction In article 2202932 by María Sancho-Albero, Luisa De Cola, and co-workers, a prodrug, based on a Pt(IV) complex, encapsulated in a nanocage, is activated upon the destruction of the carrier and exerts antitumoral activity in hard-to-treat mesothelioma cancer.
Printed Silk Microelectrode Arrays for Electrophysiological Recording and Controlled Drug Delivery (Adv. Healthcare Mater. 17/2023)
Authors: Nouran Adly, Tetsuhiko F. Teshima, Hossein Hassani, George Al Boustani, Lennart J.K. Weiß, Gordon Cheng, Joe Alexander, Bernhard Wolfrum
Journal: Advanced Healthcare Materials (2023)

Additive Manufacturing In article 2202869, Bernhard Wolfrum and co-workers develop an on-demand drug release system by using inkjet-printed silk fibroin and carbon materials for the fabrication of microelectrode arrays. The flexible silk–carbon microelectrode arrays enable in vitro extracellular recordings of cardiac action potentials as well as localized chemical stimulation.
Tongue−Brain‐Transported ZnO Nanoparticles Induce Abnormal Taste Perception (Adv. Healthcare Mater. 17/2023)
Authors: Aijie Chen, Ruolan Wang, Yiyuan Kang, Jia Liu, Junrong Wu, Yanli Zhang, Yulin Zhang, Longquan Shao
Journal: Advanced Healthcare Materials (2023)

Taste Perception In article 2203316 by Longquan Shao and co-workers, tongue–brain transported zinc oxide nanoparticles (ZnO NPs) can induce neuroinflammation in the gustatory cortex (GC), reduce synaptic transmission in neurons, and ultimately lead to abnormal taste perception. Based on this unique discovery, inhibiting neuroinflammation or enhancing synaptic transmission can provide positive effects for the treatment of taste perception abnormalities.